Roles of Gray Matter Brain Aging and Small Vessel Disease in AD Pathophysiology

In this Yr16 renewal of our longitudinal study on the natural progression of AD biomarkers, the central goal
remains to further understand the occurrence of asymptomatic amyloid-beta (Aβ) and tau deposition and the
progression to clinical cognitive impairment. This cohort has now matured to the point that there is now
sufficient longitudinal follow-up to address important hypotheses that were formulated from the beginning of
this study but could not be properly addressed until 10-15 years of follow-up were in place - as is the case now.
In this renewal period we aim to better characterize the different roles gray matter brain aging and small vessel
disease have on AD progression. Chronological age is the most salient risk factor for late-onset AD. However,
it remains unclear what components of the aging process account for this risk. In this proposal, we use gray
matter brain age models to study the atrophy-related components of aging and 7T vascular imaging to
characterize the SVD components of aging. Aim 1 uses this estimated gray matter brain age to explain
individual differences in AD biomarkers and cognitive decline. Aim 2 uses fMRI and cerebrovascular imaging
at 7T to examine the role of SVD in accelerating the amyloid-induced tauopathy and neurodegeneration. Aim
3 ties together brain aging and SVD to test components of a model that small vessel disease (SVD)
accelerates Tau deposition and neurodegeneration (including accelerated gray matter brain aging). Over the
last 2 years we have transitioned the MR imaging of this study to a 7T MR scanner to take advantage of its
high field strength for 1) characterizing small vessel morphology (e.g., early markers of cerebrovascular
disease) associated with AD risk and 2) characterizing functional neural systems (fMRI). Over the course of
this study we have shown that many (~25%) of cognitively unimpaired older adults have significant cerebral
amyloid deposition, subsequently defined as preclinical AD. We and others have shown that in this preclinical
stage, cross-sectional Ab burden is only weakly associated with objective cognitive performance. At this early
disease stage, Ab burden is more strongly associated with changes in the functional connectivity, which can be
measured by fMRI. We and others have identified that regional medial temporal lobe functional connectivity
(MTL_FC) during memory encoding is associated with increased Ab load. In recent preliminary work, we have
found that traditional markers of SVD interact with amyloid burden in their relationship to MTL_FC. Those with
high Ab and high White Matter Hyperintensity (WMH) burden have particularly high regional MTL_FC. In
individuals with Ab burden, SVD accelerates tau deposition, neurodegeneration, and progression of cognitive
and clinical decline. The current cohort of 70 active participants will be supplemented by recruitment of
additional older adults to achieve 200 baseline assessments. Individuals will undergo 3 MRI scans and 2 Ab-
and tau-PET scans over a 32-month interval.

Grant Number: 5R01AG025516-14
NIH Institute/Center: NIH
Principal Investigator: HOWARD AIZENSTEIN